Submissions for variant NM_000249.4(MLH1):c.1153C>T (p.Arg385Cys)

gnomAD frequency: 0.00005  dbSNP: rs63750760

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524225	SCV000262140	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 385 of the MLH1 protein (p.Arg385Cys). This variant is present in population databases (rs63750760, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10348818, 15222003, 27732944, 30309722, 31118792, 31386297, 32710294, 35449176, 36243179). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 31118792, 31784484). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075124	SCV000266073	uncertain significance	Lynch syndrome	2017-07-11	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490290	SCV000267395	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-03-18	criteria provided, single submitter	reference population
Ambry Genetics	RCV000217569	SCV000273951	likely benign	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656862	SCV000565154	likely benign	not provided	2021-09-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31386297, 31118792, 30309722, 27732944, 26845104, 10348818, 28706299, 29419868, 28822769, 29192238, 29258903, 28724667, 27071721, 26010451, 27683556, 25148578, 27311873, 24918944, 27831900, 24549055, 14514376, 24362816, 18383312, 25115387, 15222003, 11839723, 31127692)
Color Diagnostics, LLC DBA Color Health	RCV000217569	SCV000684720	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant leads to a MLH1 protein level and mismatch repair activity that are comparable to the wild-type control in a cell-based assay (PMID: 31784484). This variant has been reported in individuals affected with gastric cancer (PMID: 10348818), colon cancer (PMID: 11839723, 15222003, 25110875), and pancreatic cancer (PMID: 27732944) and in individuals having a personal and/or family history of breast and/or ovarian cancer (PMID: 24549055, 24918944, 26010451, 26845104). This variant has also been identified in 15/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in the Chinese general population (PMID: 34172528). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000202088	SCV000711742	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg385Cys variant in MLH1 has been reported in at least 2 individuals with MLH1-associate d cancers and segregated with disease in multiple relatives from 1 family (Cravo 2002, Lage 2004, Chao 2008, Shirts 2016). This variant has also been identified in 3/8648 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750760). This frequency is low enough to be consistent with the frequency of Lynch syndrome in the general population. Computational prediction tools and conservation analysis suggest that the p.Arg 385Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Arg385Cys variant is unc ertain.
Fulgent Genetics, Fulgent Genetics	RCV000764489	SCV000895560	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202088	SCV000919636	uncertain significance	not specified	2021-08-13	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1153C>T (p.Arg385Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 377464 control chromosomes, predominantly at a frequency of 0.00078 within the East Asian subpopulation in the gnomAD database and Japanese control databases (HGVD and jMorp). The observed variant frequency within East Asian control individuals is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1153C>T has been reported in the literature in individuals affected with different types of cancer including Lynch/colorectal cancer, breast cancer and FAP (e.g. Cravo_2002, Lage_2004, Castera_2014, Shirts_2016, Sun_2017, Shang_2018, Wardell_2018, Kiyozumi_2019, Wang_2019, Chen_2020, Horiuchi_2020, Dorling_2021) but it was also reported in unaffected controls (Dorling_2021). One of these studies reports the variant segregated with colorectal cancer phenotype in most instances in a family, except from two family members (aged 62 and 30 years) who had the variant and were healthy (Cravo_2002). Other studies report co-occurrences with pathogenic variants, providing supporting evidence for a benign role. Particularly the variant was reported to co-occur with APC c.637C>T (p.R213X) in one individual affected with FAP (Shang_2018) and with TP53 c.1010G>A (p.Arg337His) in one individual affected with breast cancer (Wang_2019). Experimental evidence evaluating an impact on protein function demonstrated no damaging effect of this variant (Gong_2019, Houlleberghs_2020). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030628	SCV001193610	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149731	SCV003838211	uncertain significance	Breast and/or ovarian cancer	2022-05-02	criteria provided, single submitter	clinical testing
Mendelics	RCV003492407	SCV004232565	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202088	SCV000257044	uncertain significance	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656862	SCV001549889	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Arg385Cys variant was identified in 9 of 8796 proband chromosomes (frequency: 0.001) from individuals or families with colon, breast, ovarian, pancreatic or gastric cancer, and was not identified in 100 control chromosomes from healthy individuals (Castera 2014, Cravo 2002, Lage 2004, Natarajan 2016, Shirts 2015, Stenzinger 2014, Takai 2016, Wong 2016, Yamamoto 1999). The variant was also identified in dbSNP (ID: rs63750760) as "With Likely pathogenic allele", ClinVar (classified as uncertain significance by InSight, Invitae, Ambry Genetics, GeneDx, Color Genomics, and three clinical laboratories; as likely pathogenic by University of Washington Department of Laboratory Medicine), in Cosmic (6x in Haematopoietic and lymphoid tissue, skin, Large intestine or NS), MutDB, UMD-LSDB (2x as unclassified variant), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors databases. The variant was not identified in COGR, or Zhejiang University databases. The variant was identified in control databases in 13 of 246188 chromosomes at a frequency of 0.000053 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15300 chromosomes (freq: 0.00006), Latino in 1 of 33578 chromosomes (freq: 0.00003), European in 2 of 111650 chromosomes (freq: 0.00002), East Asian in 8 of 17248 chromosomes (freq: 0.0005), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, and Finnish populations. By a multivariate Analysis of Protein Polymorphisms–Mismatch Repair system, the variant was classified as uncertain significance (Chao 2008). The p.Arg385 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.